Treatment of fibromyalgia

ABSTRACT

A method of using N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine to treat persistent pain.

This is a 371 of PCT/US99 filed Sep. 10, 1999.

The invention relates to a method for usingN-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine (hereinafterreferred to as “duloxetine”) for the treatment of persistent pain.

For some years, it has been recognized that the chemistry of serotoninand norepinephrine are extremely important in neurological processes,and pharmacologists and medical researchers have been very activelystudying the mechanisms of those neurotransmitters in the brain.Concomitantly, the synthesis and study of pharmaceuticals which affectserotonin and norepinephrine processes in the brain are of greatinterest and are also being intensively studied, both by pharmaceuticalchemists and by medical researchers as well.

Duloxetine inhibits the reuptake of both serotonin and norephinephrine,and is being investigated for use as an antidepressant.3-aryloxy-3-substituted propanamines, such as duloxetine, have beendisclosed in U.S. Pat. No. 5,023,269 as being useful for the treatmentof pain. This patent, however, does not specify what forms of pain aretreated. PCT/US95/13289 discloses that duloxetine is useful for thetreatment and prevention of neuropathic pain and migraine. As statedtherein, “Neuropathic pain, as distinct from other varieties of pain,emanates specifically from a neurologic source, as from a nerve which isunnaturally stressed, compressed or otherwise injured, it does notinclude pain emanating from an injury or inflammation of bone, muscle orother tissue.” PCT/US95/13289 defines migraine “as a headache,particularly a very severe headache, which occurs repetitively inpatients subject to the condition. It has been treated with partialsuccess with vasoconstrictors but no treatment of migraine in the priorart is reliably successful.”

For clinical purposes, pain may be divided into two categories: acutepain and persistent pain. Acute pain is provoked by noxious stimulationproduced by injury and/or disease of skin, deep somatic structures orviscera, or abnormal function of muscle or viscera that does not produceactual tissue damage. On the other hand, persistent pain can be definedas pain that persists beyond the usual course of an acute disease or areasonable time for an injury to heal or that is associated with achronic pathologic process that causes continuous pain or the painrecurs at intervals for months or years. If pain is still present aftera cure should have been achieved, it is considered persistent pain. Forthe purpose of the present invention, persistent pain can be chronicnon-remitting or recurrent. The difference in definition between acuteand persistent pain is not merely semantic but has an important clinicalrelevance. For example, a simple fracture of the wrist usually remainspainful for a week to 10 days. If the pain is still present beyond thetypical course of treatment, it is likely that the patient is developingreflex sympathetic dystrophy, a persistent pain syndrome that requiresimmediate effective therapy. Early and effective interventionpotentially prevents the undue disability and suffering, and avoids thepotential development of a condition that becomes refractory to therapy.

Acute and chronic pain differ in etiology, mechanisms, pathophysiology,symptomatology, diagnosis, therapy, and physiological responses. Incontrast to the transitory nature of acute pain, persistent pain iscaused by chronic pathologic processes in somatic structures or viscera,by prolonged and sometimes permanent dysfunction of the peripheral orcentral nervous system, or both. Also, persistent pain can sometimes beattributed to psychologic mechanisms and/or environmental factors.

Persistent pain is a disease state that is one of the most importanthealth problems in industrialized nations throughout the world.Persistent pain and suffering, regardless of cause, has seriousphysical, behavioral, mental, psychologic, social, and economic effectson both the patient and the family, and is very costly to society.

The mental effects of prolonged or persistent pain are greatlyinfluenced by the duration, intensity, and periodicity of the persistentpain, by the personality and psychologic makeup of the individual, andby various socioloaic and economic factors. The duration of thepersistent pain is an important factor in determining the mentaleffects; for while the average individual can briefly bear, bothpsychologically and physiologically, even the most severe pain, if suchpain is prolonged it exerts effects which cause mental and physicaldeterioration. Prolonged, persistent, and intense pain interferes withthought processes and dominates the entire organism.

The impact of persistent pain on society is equally devastating as itseffects on the sufferer. Patients develop problems with their familiesand friends, and, as previously mentioned, decrease their socialinteractions. Household chores (cooking, caring for a sick child, etc.),social and familial obligations are frequently cancelled. Some patientsare unable to work, some are ineffective at work, others are encouragednot to work, and still others lose their jobs because of frequentabsences. In fact, the unemployment rate of some chronic pain conditionscan be 4-5 times higher than the average unemployment rate in the UnitedStates. These profound societal effects may render the patient aneconomic liability rather than an asset.

Current therapies for persistent pain include opiates, barbiturate-likedrugs such as thiopental sodium and surgical procedures such asneurectomy, rhizotomy, cordotomy, and cordectomy. These therapies havesignificant drawbacks. Opiates and barbiturate-like drugs have limitingside effects and are addictive. Tricyclic antidepressants andanticonvulsants are marginally effective, and also are associated withsome limiting side effects. Electrical stimulation, e.g., TENS haslimited success in chronic pain. Surgical procedures are expensive,irreversible and often fail to provide long-term relief from persistentpain. Faced with suboptimal therapy for persistent pain, the patientsuffers more, complains more, and becomes more desperate anddissatisfied with their healthcare. As a consequence, the patient seeksand consumes more direct and indirect healthcare resources.

In light of these realities, there is a demand for more effectiveanalgesic agents, targeted specifically for persistent pain, which havea superior safety and tolerability profile and are non-addictive. Theideal analgesic would reduce the awareness of pain, produce analgesiaover a wide range of pain types, act satisfactorily whether given orallyor parenterally, produce minimal or no side effects, and be free from atendency to produce tolerance and drug dependence.

The present invention addresses the need for a safe and effectivetreatment of persistent pain by providing a method of treatingpersistent pain.

In accordance with the present invention, there is provided a method oftreating persistent pain comprising the administration to a patient inneed of such treatment of an effective amount of duloxetine.

The present invention also provides the use of duloxetine for themanufacture of a medicament for treating persistent pain.

Furthermore, the present invention provides the use of duloxetine fortreating persistent pain.

The term “treating” for purposes of the present invention, includesprophylaxis or prevention, amelioration or elimination of a namedcondition once the condition has been established.

The term “patient” for purposes of the present invention is defined asany warm blooded animal such as, but not limited to, a mouse, guineapig, dog, horse, or human. Preferably, the patient is human.

For purposes of the present invention, the term “acute pain” is definedas pain which is provoked by noxious stimulation produced by injuryand/or disease of skin, deep somatic structures or viscera, or abnormalfunction of muscle or viscera that does not produce actual tissuedamage.

The term “persistent pain” as used herein, is defined as pain thatpersists beyond the usual course of an acute disease or a reasonabletime for an injury to heal or that is associated with a chronicpathologic process that causes continuous pain or the pain recurs atintervals for months or years. If pain is still present after a cureshould have been achieved or beyond a typical course of treatment, it isconsidered persistent pain. The length of time that must pass beforepain is persistent depends upon the nature of the pain and the typicalcourse of treatment associated with the pain. Pain is persistent if itlasts beyond a typical course of treatment.

Persistent pain includes, but is not limited to, tension-type headache,musculoskeletal pain, pain associated with somatoform disorders,visceral pain, painful diabetic neuropathy, vascular pain, arthriticpain, back pain, neck pain, shoulder pain, cancer pain, pain associatedwith AIDS, postoperative pain, and post-burn pain.

Duloxetine is effective in treating persistent pain as defined above.Also, duloxetine is useful in treating other conditions where there ishyper-sensitization to painful signals, hyperalgesia, allodynia,enhanced pain perception, and enhanced memory of pain. Duloxetine willimprove coping with pain.

Tension-type headache is the most common form of primary or idiopathicheadaches, i.e. those that are not related to an identifiable cause. Twotypes of tension-type headaches are recognized; episodic tension-typeand chronic tension-type. “Chronic tension-type headache” as usedherein, is defined by International Headache Society criteria(Cephalalgia 1988;8 (Suppl 7): 1-96) as recurrent headaches that are“present for at least 15 days a month during at least 6 months. Theheadache is usually pressing/tightening in quality, mild or moderate inseverity, bilateral and does not worsen with physical activity. Nausea,photophobia or phonophobia may occur.”

Chronic tension-type headache (TTH) occurs in 2-3% of the population.The severity of the pain of TTH, unlike that of episodic TTH, is usuallymoderate to severe. Chronic TTH is differentiated from migraineclinically based on the following features: bilaterality of pain;non-pulsating quality; often varying locations of pain; seldomassociation with both light (photophobia) and noise (phonophobia)sensitivity. In addition, smell sensitivity (osmophobia) is not asymptom of TTH; absence of neurological accompaniments such as visual orsensory auras.

“Somatoform disorders,” as used in the present invention, are defined ashaving, as a common feature, the presence of physical symptoms thatsuggest a general medical condition which are not fully explained by ageneral medical condition, by the direct effects of a substance, or byanother mental disorder. (Diagnostic and Statistical Manual of MentalDisorders, 4^(th) edition, p. 445). Somatoform disorders includefunctional somatic syndromes, including those referenced in Barsky A J,Borusn J F. Functional Somatic Syndromes. Ann Intern Med1999;130:910-921, such as, but not limited to, multiple chemicalsensitivity, sick building syndrome, repetition stress injury, chronicwhiplash, chronic lime disease, side effects of silicon breast implants,candidiasis hypersensitivity, the Gulf War Syndrome, food allergies,mitral valve prolapse, and hypoglycemia.

The term “musculoskeletal pain” as used herein, includes, but is notlimited to, myofascial pain, trauma-induced pain, and chronic regionalpain syndrome.

The term “myofascial pain” as used herein, includes, but is not limitedto, temporo-mandibular joint disease (TMJ) and fibromyalgia with orwithout chronic fatigue syndrome. The term “fibromyalgia”, for purposesof the present invention, includes, but is not limited to, that painwhich is defined by the American College of Rheumatology (ACR)classification (Wolf F, et al., The American College of Rheumatology1990 criteria for the classification of fibromyalgia: Report of theMulticenter Criteria Committee. Arthritis Rheum 33:160-172;1990.)Fibromyalgia is a clinical syndrome characterized by chronic muscleaches, stiffness, fatigue, non-restorative sleep, and localized tenderpoints. The ACR criteria for fibromyalgia are: 1) widespead aching inall four quadrants and in the axial skeleton for more than least 3months in duration; and 2) pain in 11 or more of 18 tender points underdigital pressure examination.

For the purposes of the present invention, “painful diabetic neuropathy”is pain which is secondary to injury to nerves as a complication ofdiabetes mellitus. Injury to nerves in diabetes mellitus is caused, atleast in part, by decreased blood flow and high blood-sugar levels. Somediabetics will not develop neuropathy, while others may develop thiscondition relatively early. Diabetic neuropathies may be classified intomononeuropathies involving one or more focal sites and generalizedpolyneuropathies which may be diffuse, symmetric and often predominantlyinvolving sensory modalities [Merrit's Textbook of Neurology, 9th ed.,ed by L. P. Rowland, Williams and Wilkins, 1995, p. 669]. Manifestationsof diabetic neuropathy can include dysfunction of autonomic nervesresulting in dysregulation of vital functions including the heart,smooth muscles, and glands. Low blood pressure, diarrhea, constipation,and sexual impotence also result from autonomic neuropathies. Cranialneuropathies may affect vision. Sensory neuropathies affect the nervesthat carry sensory information from the skin and other sense organs tothe brain. Loss of sensation of touch, pressure, vibration andtemperature to a body part or area may result from sensory neuropathies.Diabetic neuropathies are sometimes, but not always, accompanied bypain. Painful diabetic neuropathy tends to develop in stages. Early on,intermittent pain and tingling may be noted in the extremities of nerveterminal fields, particularly the feet in the case of autonomic orsensory neuropathy, or in the face and around the eye in the case ofcranial neuropathy. In later stages, the pain is more intense andconstant. Finally, a painless neuropathy develops when pain sensation islost to an area, which greatly increases the risk of severe tissueinjury without pain as an indicator of injury.”

The term “visceral pain” includes, but is not limited to that painassociated with irritable bowel syndrome (IBS) with or without chronicfatigue syndrome (CFS), inflammatory bowel disease (IBD), andinterstitial cystitis.

The term “vascular pain”, for purposes of the present invention, is thatpain “produced by one or more of the following pathophysiologic factors:(a) inadequate perfusion of tissues with consequent transient orcontinuous ischemia such as occurs in the muscles of the limb duringexercise, ischemia of the skin that produces rest pain, and ischemia ofa viscus such as the heart or gastrointestinal tract; (b) secondarychanges such as ulcerations or gangrene in the skin or abdominalviscera; (c) sudden or accelerated changes in the vascular dimension oflarge vessels such as occurs with aneurysm; (d) rupture of the aortawith consequent spillage of blood that stimulates nociceptive fibers inthe parietal peritoneum or parietal pleura; (e) intense spasm consequentto the intra-arterial injection of severe irritant on the endothelium ofthe artery; and (f) impairment of venous return with consequent massiveedema that rapidly stretches fascial compartments”. (J. J. Bonica etal., The Management of Pain Vol. 1 (2nd ed., Philadelphia: Lea &Febiger, 1990.) Examples include, but are not limited to,arteriosclerosis obliterans, thromboangitis obliterans, acute arterialocclusion, embolism, congenital arteriovenous aneurysm, vasospasticdisease, Raynaud's disease, acrocyanosis, acute venous occlusion,thrombophlebitis, varicose veins, and lymphedema.

The term “arthritic pain” includes, but is not limited to,osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, Reiter'ssyndrome, psoriatic arthritis, gout, pseudogout, infectious arthritis,tendonitis, bursitis, bone lesions and joint soft tissue inflammation.

For purposes of the present invention, “nociceptive pain” is pain causedby a tissue-damaging process that excites nociceptive afferents or painwhich is provoked by prolonged excitation of nociceptors. Persistentpain which arises from nociceptive pain may be due to persistent noxiousstimulation of nociceptors or their sensitizations or both, or they maybe initiated by these factors and prolonged by their persistence, byvarious reflex mechanisms and by other factors.

The term “nociception” as used herein refers to the neural mechanisms bywhich noxious stimuli are detected. Nociception involves two steps:transductions of noxious stimuli by peripheral nerve endings andtransmission of these signals to the central nervous system.

The present invention is useful for the treatment of nociceptive pain orpain that arises from a combination of nociceptive and neuropathicetiologies. It is preferred that the pain to be treated is nociceptivepain.

It is also believed by those of ordinary skill in the art that centralsensitization contributes to the expression of persistent pain. The term“central sensitization” as used herein is defined as hyperexcitabilityof spinal neurons.

Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, isusually administered as the hydrochloride salt and as the (+)enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which showsits high potency in the inhibition of serotonin and norepinephrineuptake. The term “duloxetine” as used herein, refers to any acidaddition salt or the free base of the molecule.

Duloxetine is a safe drug, and its use in the treatment of persistentpain is a superior treatment because of its improved safety. Thecompound is particularly selective, having few if any physiologicaleffects besides those on norepinephrine and serotonin processing, andtherefore is free of side effects and unwanted activities, unlike thelimiting side effects of other similar drugs used for the treatment ofpersistent pain. Further, it is effective at relatively low doses, asdiscussed below, and may safely and effectively be administered once perday. Thus, difficulties created by the multiple dosing of patients arecompletely avoided.

The effective amount or dose of duloxetine for treating persistent painis in the range from about 1 mg/day to about 200 mg/day. The preferredadult dose is in the range from about 40 to about 150 mg/day, and a morehighly preferred adult dose is from about 60 to about 120 mg/day. Theoptimum dose for each patient, as always, must be set by the physicianin charge of the case, taking into account the patient's size, othermedications which the patient requires, severity of the persistent painand all of the other circumstances of the patient.

Since duloxetine is readily orally absorbed and requires only once/dayadministration, there is little or no reason to administer it in anyother way than orally. It is produced in the form of a clean, stablecrystal, and thus is easily formulated in the usual oral pharmaceuticalforms, such as tablets, capsules, suspensions, and the like. The usualmethods of pharmaceutical scientists are applicable. It may usefully beadministered, if there is any reason to do so in a particularcircumstance, in other pharmaceutical forms, such as, but not limitedto, injectable solutions, depot injections, suppositories and the like,which are well known to and understood by pharmaceutical scientists. Itwill substantially always be preferred, however, to administerduloxetine as a tablet or capsule and such pharmaceutical forms arerecommended.

A preferred duloxetine enteric formulation as disclosed in U.S. Pat. No.5,508,074, which is hereby incorporated by reference, is a pelletformulation comprising a) a core consisting of duloxetine and apharmaceutically acceptable excipient; b) an optional separating layer;c) an enteric layer comprising hydroxypropylmethylcellulose acetatesuccinate (HPMCAS) and a pharmaceutically acceptable excipient; d) anoptional finishing layer. The following example demonstrates thepreparation of a preferred such formulation.

EXAMPLE

10 mg Duloxetine base/capsule Bill of Materials Beads Sucrose-starchnonpareils, 20-25 mesh 60.28 mg Duloxetine layer Duloxetine 11.21 mgHydroxypropylmethylcellulose 3.74 mg Separating layerHydroxypropylmethylcellulose 2.51 mg Sucrose 5.00 mg Talc, 500 mesh10.03 mg Enteric layer HPMCAS, LF grade, Shin-Etsu Chemical 25.05 mgCo., Tokyo, Japan Triethyl citrate 5.00 mg Talc, 500 mesh 7.52 mgFinishing layer Hydroxypropylmethylcellulose 8.44 mg Titanium dioxide2.81 mg Talc Trace 141.60 mg

The duloxetine layer was built up by suspending duloxetine in a 4% w/wsolution of the hydroxypropylmethylcellulose in water, and milling thesuspension with a CoBall Mill (Fryma Mashinen AG, Rheinfelden,Switzerland) model MS-12. A fluid bed dryer with a Wurster column wasused to make this product, at a batch size of 1.0 kg. The separatinglayer was added from a 4% w/w solution of thehydroxypropyl-methylcellulose in water, in which the sucrose was alsodissolved.

In order to prepare the enteric coating suspension, purified water wascooled to 10° C. and the polysorbate, triethyl citrate and siliconeemulsion were added and dispersed or dissolved. Then the HPMCAS and talcwere added and agitated until homogeneity was obtained, and the HPMCASwas fully neutralized by addition of ammonium hydroxide until solutionof the polymer was complete. To this suspension, acarboxymethylcellulose aqueous solution, 0.5% w/w, was added and blendedthoroughly. The enteric suspension was maintained at 20° C. during thecoating process. The enteric suspension was then added to the partiallycompleted pellets in the Wurster column at a spray rate of about 15ml/min, holding the temperature of the inlet air at about 50° C. Theproduct was dried in the Wurster at 50° C. when the enteric suspensionhad been fully added, and then dried on trays for 3 hours in a dry houseat 60° C. A finishing layer was then applied which consisted of a 4.5%w/w/hydroxypropylmethyl-cellulose solution containing titanium dioxideand propylene glycol as plasticizer. The pellets were completely driedin the fluid bed dryer and then were then filled in size 3 gelatincapsules.

Example I

The analgesic effect of duloxetine for the treatment of persistentnociceptive pain was demonstrated using the well-known “formalin test.”The formalin test is a model of persistent nociceptive activationinduced by tissue injury which can lead to central sensitization.(Shibata, M., Ohkubo, T., Takahashi, H., and Inoki, R., “Modifiedformalin test: Characteristic biphasic pain response,” Pain (1989) 38:347-352; and Tjolsen, A., Berge, O. G., Hunskaar, S., Rosland, J. H.,and Hole, K., “The formalin test: an evaluation of the method,” Pain(1992) 51:5-17.) The effect of duloxetine on formalin-inducedpaw-licking behavior in the rat was investigated as an index ofpersistent nociceptive activation. In this test, the injection offormalin under the skin on the dorsal lateral surface of the hind paw ofrats causes an immediate and intense increase in the spontaneousactivity of C fiber afferents. This activation evokes a distinctlyquantifiable behavior indicative of pain, such as licking, flinching,shaking or biting of the injected paw. The behavioral response toformalin is biphasic, with an early phase that is short lived, followedby an extended tonic response or late phase of persistent nociceptiveactivation. Mechanisms causing the late phase response, such as centralsensitization of pain transmitting neurons, are currently believed tocontribute to various types of persistent pains.

Male Sprague-Dawley rats (200-250 g; Charles River, Portage, Mich.) weremaintained at constant temperature and light (12 h light/12 h dark) for4-7 days prior to the studies. Animals had free access to food and waterat all times prior to the day of the experiment.

The formalin test was performed in custom made Plexiglas® boxes 25×25×20cm (length×width×height) in size. A mirror placed at the back of the boxallowed the unhindered observation of the formalin injected paw. Ratswere acclimatized individually in the cubicles at least 1 hour prior tothe experiment. All testing was conducted between 08:00 and 14:00 hr andthe testing room temperature was maintained at 21-23° C. Test compoundwas administered 30 or 60 minutes prior to the formalin injection.Formalin (50 μl of a 5% solution in saline) was injected subcutaneouslyinto the dorsal lateral surface of the right hind paw with a 27 gaugeneedle. Observation started immediately after the formalin injection.Formalin-induced pain was quantified by recording in 5 minute intervalsthe number of formalin injected paw licking events and the number ofseconds each licking event lasted. These recordings were made for 50minutes after the formalin injection. After the experiment, animals werekilled with an overdose of CO2. (Euthanasia protocol, Eli Lilly AnimalUse and Care Committee.)

Scoring in the formalin test was performed according to Coderre et al.,1993b and Abbott et al., 1995. (Coderre T. J., Fundytus M. E., McKennaJ. E., Dalal S. and Melzack R. “The formalin test: a validation of theweighted-scores method of the behavioral pain rating,” Pain(1993b) 54:43-50; and Abbott F. V., Franklin K. B. J. and Westbrook R. F. “Theformalin test: scoring properties of the first and second phases of thepain response in rats,” Pain (1995) 60: 91-102.) The sum of time spentlicking in seconds from time 0 to 5 minutes was considered the earlyphase while the late phase was taken as the sum of seconds spent lickingfrom 15 to 40 minutes.

Data are presented as means with standard errors of means (±SEM). Datawere evaluated by one-way analysis of variance (ANOVA) and theappropriate contrasts analyzed by Tukey's test and Dunnett “t” test fortwo-sided comparisons.

Treatment Early Phase Late Phase vehicle (i.p.)* 31.33 ± 8.04 386.22 ±40.13 duloxetine(i.p.)* (−30 min)  3 mg/kg 32.78 ± 15.97 254.00 ± 45.8710 mg/kg 17.00 ± 5.83 163.89 ± 54.14*** 15 mg/kg 29.56 ± 16.30  80.44 ±36.22*** vehicle (p.o.)** 10.71 ± 3.17 376.71 ± 36.93 duloxetine(p.o.)**(−60 min)  3 mg/kg 21.78 ± 5.14 393.56 ± 26.74 10 mg/kg 20.22 ± 5.29255.78 ± 38.22*** 20 mg/kg 12.67 ± 3.61 161.11 ± 31.77*** *(i.p.):intraperitoneal **(p.o.): oral ***p < 0.05 significantly differentcompared to vehicle control of group.

As illustrated above, duloxetine blocks the late phase response toformalin in a dose-dependent manner. These results demonstrate thatduloxetine is effective in treating nociceptive pain which ispersistent.

Example II

The tendency of duloxetine to induce ataxia or neuromuscular effects atanalgesic doses was investigated using the well-known rotorod test.

Male Sprague-Dawley rats (200-250 g; Charles River, Portage, Mich.) weremaintained at constant temperature and light (12 h light/12 h dark) for4-7 days prior to the studies. Animals had free access to food and waterat all times prior to the day of the experiment.

An automated accelerating rotorod (Omnitech Electronics Inc., Columbus,Ohio) connected to an IBM PC computer was utilized. For training andtesting purposes, the rotorod was set up to accelerate to 17 r.p.m. in 5seconds and maintaining that speed for 40 seconds. Rats were given 3training trials to learn to maintain posture on the rotorod prior to theactual day of drug testing. The following day, rotorod testing wasconducted both at 30 and 80 minutes for i.p. and at 60 and 110 minutesfor p.o. following administration of drug or compound. Animals thatmaintained posture and did not fall off the rotorod were given a maximumscore of 40 seconds.

All data were analyzed using the JMP statistical program. Data arepresented as means with standard errors of means (±SEM). Data wereevaluated by one-way analysis of variance (ANOVA) and the appropriatecontrasts analyzed by Tukey's test and Dunnett “t” test for two-sidedcomparisons.

Ataxia score, 30 Ataxia score 80 mins after drug, mins after drug,Treatment i.p.* i.p.* vehicle (i.p.)* 30.99 ± 4.11 30.99 ± 4.11duloxetine(i.p.)* (−30 min)  3 mg/kg 34.27 ± 4.02 33.35 ± 3.23 10 mg/kg29.42 ± 6.71 26.07 ± 6.24 30 mg/kg 24.75 ± 6.88 25.52 ± 5.89 AtaxiaScore, 60 Ataxia score 110 mins after drug, mins after drug, Treatmentp.o.** p.o.** vehicle (p.o.)** 38.68 ± 1.97 38.68 ± 1.97duloxetine(p.o.)** (−60 min)  3 mg/kg 40.00 ± 0.00 40.00 ± 0.00 10 mg/kg39.11 ± 0.89 39.56 ± 0.44 20 mg/kg 40.00 ± 0.00 40.00 ± 0.00 *(i.p.):Intraperitoneal **(p.o.): oral

As demonstrated above, duloxetine did not show ataxia or neuromusculareffects in the rotorod test at doses that caused analgesia.

Example III

The analgesic effect of duloxetine for the treatment of neuropathic painis demonstrated using the well-known “Seltzer Model” which involvespartial ligation of the sciatic nerve. (Seltzer, Z., Dubner, R. andShir, Y., “A novel behavioral model of neuropathic pain disordersproduced in rats by partial sciatic nerve injury,” Pain, 43 (1990)205-218.) This model mimics the major clinical symptoms of causalgia,which are rapid onset of hyperalgesia and allodynia.

Young adult male Sprague Dawley rats from Harlan (Indianapolis, Ind.)weighing 135-155 g were housed in groups of 3-4 in plastic cages withsoft bedding under a 12/12 h day/night cycle. Rats were placed in aprone position under gaseous isofluorane anesthesia. Surgery wasperformed on the left upper thigh as described by Seltzer et al., 1990.The sciatic nerve was carefully exposed by separating the muscles aboveit with a small retractor. The dorsal third to half of the nerve wastightly ligated with a 4.0 silk suture at a sight distal to the point atwhich the posterior biceps-semitendinosus nerve branches off. The woundsite was sutured back according to animal protocol procedures. Animalswere then allowed to recover and placed back into their cages. The ratsrecovered sufficiently from the surgical procedures to resume normalactivity within 30 min after termination of the gaseous anesthesia.

Beginning at 24 hours following recovery from surgery, the painsensitivity of the hind paw was analyzed using von Frey filamentsapplied to both the surgical and contralateral paw surfaces. In thismethod, a brisk foot withdrawal in response to normally innocuousmechanical stimuli was measured. (Kim, S. H. and Chung, J. M., “Anexperimental model for peripheral neuropathy produced by segmentalspinal nerve ligation in the rat,” Pain, 50 (1992) 355-363.) Innocousmechanical stimuli were applied with von Frey filaments of differentbending forces (corresponding to grams of force ranging from 1-15 g).The rat was placed in a plexiglass box with a metal mesh floor and thevon Frey filaments were applied to the plantar surface of the foot. Avon Frey filament was applied perpendicular to the plantar surface withsufficient force to cause slight bucking against the paw, and held for2-3 seconds to each hind paw. A positive response is noted if the paw issharply withdrawn. The threshold (gram force) to cause foot withdrawalsin response to the filament was expressed as Response (g) andcalculations to arrive at this were based on the method of Dixon, W. J.,Efficient analysis of experimental observations, Ann. Rev. Pharmacol.Toxicol. 20:441-462, 1980. Stimulation of normal human skin with theweak (4.3 nM) and strong (5.18 nM) von Frey filaments elicitsrespectively, a weak sense of touch and a sense of pressure. Therefore,a significant change in the sensory threshold causing brisk footwithdrawals in response to these innocuous mechanical stimuli is due todevelopment of mechanical allodynia due to the nerve ligation. Theresponse (g) (mechanical stimuli) was plotted against test doses of drugor vehicle. While the paw on the surgical side develops mechanicalallodynia, the paw on the contralateral non-surgical side remains normaland serves as a control.

All data were analyzed using the JMP statistical program. Data werepresented as means with standard errors of means (±SEM). Data wereevaluated by one-way analysis of variance (ANOVA) and the appropriatecontrasts analyzed by Tukey's test and Dunnett “t” test for two-sidedcomparisons.

Treatment Allodynia Response (g) No nerve ligation vehicle (i.p.*,p.o.**)   15 ± 0.0 (no allodynia) Nerve ligation vehicle (i.p.*) 2.18 ±0.31 duloxetine (15 mg/kg, 8.57 ± 1.72*** i.p.*, 1 hour pretreatment)vehicle (p.o.**) 3.45 ± 0.56 duloxetine (20 mg/kg, 8.53 ± 1.66***p.o.**, 1 hour pretreatment) duloxetine (20 mg/kg × 9.18 ± 2.95*** 4day, p.o.**, sub- chronic pretreatment) intraperitoneal(i.p.)* or oral(p.o.)** and after sub-chronic oral dosing of duloxetine once a day forfour consecutive days; ***p < 0.05 significantly different compared tovehicle control of group.

As illustrated above, duloxetine attenuates the allodynia developedfollowing partial ligation of the sciatic nerve after acute orsub-schronic systemic administration. These results demostrate thatduloxetine is effective in the treatment of neuropathic pain.

We claim:
 1. A method of treating fibromyalgia comprising administeringto a patient in need of treatment an effective amount of duloxetine. 2.The method of cliam 1 wherein duloxetine is(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanaminehydrochloride.